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Abstract Fzf1 is a Saccharomyces cerevisiae transcription factor containing five zinc fingers (ZFs). It regulates the expression of at least five downstream genes, including SSU1, YHB1, DDI2/3, and YNR064c, by recognizing a consensus sequence, CS2, found in these gene promoters. These gene products are involved in cellular responses to various chemical stresses. For example, SSU1 encodes a sodium sulfite efflux protein that confers sulfite resistance. However, the underlying molecular mechanism through which Fzf1 responds to chemical stress and coordinates target gene activation remains elusive. Interestingly, several mutations in the fourth ZF (ZF4) of Fzf1 have previously been reported to confer either sulfite resistance or elevated basal‐level expression of YHB1, indicating that ZF4 negatively impacts Fzf1 activity. Since ZF4 is dispensable for CS2 binding in vitro, we hypothesized that ZF4 is a negative regulator of Fzf1 and that chemically induced Fzf1‐regulated gene expression occurs via de‐repression. All five genes examined were cross‐induced by corresponding chemicals in an Fzf1‐dependent manner, and all three ZF4 mutations and a ZF4 deletion conferred increased basal‐level expression and SSU1‐dependent sulfite resistance. A ZF4 deletion did not alter the target DNA binding, consistent with the observed codominant phenotype. These observations collectively reveal that Fzf1 remains inactive by default at the target promoters and that its activation is at least partially achieved by self‐derepression through chemical modification and/or a conformational change.

Key Clinical Message Herpes zoster is an acute cutaneous viral disease resulting from reactivation of dormant varicella‐zoster virus. The maxillary nerve is the least frequently affected branch of the trigeminal nerve. Rarely, cutaneous lesions can be secondarily infected with Klebsiella species. This report discusses a case of maxillary zoster with nasociliary nerve involvement and Klebsiella superinfection.

Background: Problem-solving as a vehicle to develop independent thinking skills is mostly underestimated and is often either overlooked or not given adequate attention within the existing South African mathematics curriculum. Consequently, numerous learners often display limited skills or lack skills to adequately crack Mathematics problems by applying methods put forward in class. This generally results in under-achievement. Aim: This study aims to explore and emphasise the problem-solving methods applied by Grade 4 learners involved in solving measurement word problems, and to reveal what transpires when the selected learners apply these methods to arrive at meaningful solutions. Setting: Data were collected from a class of 42 Grade 4 learners at a primary school in Cape Town South Africa. Learners were conveniently selected. Methods: A qualitative case study research design was adopted. Data gathering instruments of the study included observing learners solving, measurement word problem activities and focus group interviews. Results: The study revealed that singular methods were applied by Grade 4 learners, such as, adding, multiplying, creating a sketch or diagram, grouping, dividing, subtracting, logical reasoning, guessing and tabulating values. Conclusion: Grade 4 learners are prone to applying methods such as clustering or organising into groups, tabulating numerical values and logical reasoning were all applying mathematically sound methods. Such learners, however, needed a degree of supervision and instruction to indicate the way in which such methods were applied successfully as these methods were not necessarily dealt with in classroom context or in textbooks. Contribution: The findings emphasise the need for tackling learners’ limited problem-solving competencies and accentuate the necessity for greater attention to develop and grow methods for optimal and successful solving of problems in context.

Abstract Manipulating the grain boundary and chiral structure of enantiomorphic inorganic thermoelectric materials facilitates a new degree of freedom for enhancing thermoelectric energy conversion. Chiral twist mechanisms evolve by the screw dislocation phenomenon in the nanostructures; however, contributions of such chiral transport have been neglected for bulk crystals. Tellurium (Te) has a chiral trigonal crystal structure, high band degeneracy, and lattice anharmonicity for high thermoelectric performance. Here, Sb‐doped Te crystals are grown to minimize the severe grain boundary effects on carrier transport and investigate the interface of chiral Te matrix and embedded achiral Sb2Te3 precipitates, which induce unusual lattice twists. The low grain boundary scattering and conformational grain restructuring provide electrical‐favorable semicoherent interfaces. This maintains high electrical conductivity leading to a twofold increase in power factor compared to polycrystal samples. The embedded Sb2Te3 precipitates concurrently enable moderate phonon scattering leading to a remarkable decrease in lattice thermal conductivity and a high dimensionless figure of merit (zT) of 1.1 at 623 K. The crystal growth and chiral atomic reorientation unravel the emerging benefits of interface engineering as a crucial contributor to effectively enhancing carrier transport and minimizing phonon propagation in thermoelectric materials.

Chilaiditi’s sign is a rare radiological finding characterized by colonic interposition between the liver and the right hemidiaphragm. It is a cause of pseudopneumoperitoneum which is often mistaken for true pneumoperitoneum. In this article, we present the case of a 73-year-old female with a previous history of pulmonary tuberculosis, who reported to our hospital with progressive abdominal distension associated with early satiety, bipedal swelling, generalized weakness, worsening fatigue, and weight loss. Following evaluation, she was diagnosed with liver cirrhosis and chronic lymphocytic leukemia. Her chest radiograph also incidentally showed air under the right hemidiaphragm with haustral folds consistent with Chilaiditi’s sign. Since she did not have signs of peritonitis, she was eventually treated for liver cirrhosis and chronic lymphocytic leukemia without undergoing any surgical intervention. This case report seeks to create awareness among clinicians about this rare radiological sign in order to prevent misdiagnosis leading to unnecessary surgical procedures.

Food commodities and energy bills have experienced rapid undulating movements and hikes globally in recent times. This spurred this study to examine the possibility that the shocks that arise from fluctuations of one market spill over to the other and to determine how time-varying the spillovers were across a time. Data were daily frequency (prices of grains and energy products) from 1 July 2019 to 31 December 2022, as quoted in markets. The choice of the period was to capture the COVID pandemic and the Russian–Ukrainian war as events that could impact volatility. The returns were duly calculated using spreadsheets and subjected to ADF stationarity, co-integration, and the full BEKK-GARCH estimation. The results revealed a prolonged association between returns in the energy markets and food commodity market returns. Both markets were found to have volatility persistence individually, and time-varying bidirectional transmission of volatility across the markets was found. No lagged-effects spillover was found from one market to the other. The findings confirm that shocks that emanate from fluctuations in energy markets are impactful on the volatility of prices in food commodity markets and vice versa, but this impact occurs immediately after the shocks arise or on the same day such variation occurs.

On 27–29th of September 2022, Wellcome convened an international multi-stakeholder workshop to discuss the use of Correlates of Protection (CoP) to accelerate vaccine development, the hybrid format meeting was attended by 80 delegates including developers, manufacturers, regulators, public health officials and policy-makers from 17 countries, including 7 LMIC’s.

AbstractThe study examines pre-service mathematics teachers’ perceptions of the integration of technology into algebra education. With the growing emphasis on technology in education, it is crucial to understand how pre-education teachers see technology and engage in it when teaching mathematics. The research aims to gain a view of their beliefs, attitudes, and experiences regarding the integration of technology into algebraic teaching, and the advantages and challenges they experience in implementing them. The study adopted the quantitative approach to research and a descriptive survey design. The purposive sampling technique was used to sample 73 respondents for the study. Descriptive and inferential statistics were used to analyze the data. The findings highlight that preservice mathematics teachers in the Upper East Region of Ghana have a strong and positive perception about technology integration and this perception does not differ by age. The study further revealed that the factors that strongly influence their perception are teacher education programs, self-efficacy, prior experience and their attitude. The results of this research can inform teacher training programs and professional development initiatives and provide valuable insights into the preparation and support required for pre-education teachers to effectively integrate technology into algebraic instruction. By understanding and addressing the views of pre-service teachers, educational stakeholders can improve their ability to use technology as a teaching tool, which will encourage more interactive and effective algebra education in the digital age.

Research suggests that beginner teachers face challenges when transitioning from pre-service to in-service teaching. Both nternational and local research found that transitioning from preservice to newly qualified teachers can be problematic. This study explores the learning experiences of beginner foundation phase Grade R teachers. The study utilises a qualitative research design embedded in the interpretivist paradigm. Data were collected from six foundation phase Grade R teachers using semi-structured interviews and reflective journals. The findings show that beginner teachers face enormous challenges early in their careers, and their sustainability in the classroom depends on how well they address these challenges. The findings have significant implications for the implementation of formal mentoring in practice.

The assessment of environmental sustainability is of utmost importance for the forests and plantations in Borneo, given the critical need for environmental protection through the identification and mitigation of potential risks. This study was conducted to assess the environmental sustainability of tropical forest and plantations landscape, a case study in northern Sabah, Malaysian Borneo. Applications of the latest high-resolution multi-sensor remote sensing and geospatial MCDA are cost-effective and useful for large-scale environmental sustainability assessment. The land use land cover (LULC) of the study area was mapped with synergistic use of Sentinel-1 Synthetic Aperture Radar (SAR) and Sentinel-2 optical and high-resolution PlanetScope satellite imageries, resulting in overall accuracy of 87.24%. Five sustainability indicator layers: slope erosion protection, river buffer, landscape connectivity and quality, high conservation value (HCV), and water turbidity were developed from the LULC map, ancillary datasets of SRTM, and forest operation basemap with reference to standards from the Environment Protection Department (EPD), Roundtable on Sustainable Palm Oil (RSPO), and Forest Management Plan (FMP) for the analysis using multi-criteria decision analysis (MCDA) model. The results revealed that overall, the study areas are in the high sustainability category at 61%, medium at 31%, and low at only 8%. We analyzed the environmental sustainability of five land use boundaries, and the results showed that Industrial Tree Plantations (ITP) and Village Reserve are mostly in the high category. Meanwhile, oil palm plantations, rubber plantations, and forest reserve (FR) are the majority in the medium category. Both oil palm and rubber plantations are a majority in the medium class due to monocropping land use type having low landscape connectivity and quality individual sustainability indicator layer. The study presented the concept of use of multi-sensor remote sensing for LULC mapping with geospatial MCDA for environmental sustainability assessment useful to stakeholders for improving the management plan also contributing toward the progress of achieving UNSDGs and addressing REDD+.

Key Clinical Message Although squirrel bites are uncommon and generally benign, they have been implicated in the transmission of certain diseases in humans, some of which can be life‐threatening. This report discusses the case of a 27‐year‐old hunter who developed a necrotizing soft tissue infection with vesiculo‐bullous skin lesions after a ground squirrel bite.

Abstract Manipulating thermal properties of materials can be interpreted as the control of how vibrations of atoms (known as phonons) scatter in a crystal lattice. Compared to a perfect crystal, crystalline solids with defects are expected to have shorter phonon mean free paths caused by point defect scattering, leading to lower lattice thermal conductivities than those without defects. While this is true in many cases, alloying can increase the phonon mean free path in the Cd‐doped AgSnSbSe3 system to increase the lattice thermal conductivity from 0.65 to 1.05 W m−1 K−1 by replacing 18% of the Sb sites with Cd. It is found that the presence of lone pair electrons leads to the off‐centering of cations from the centrosymmetric position of a cubic lattice. X‐ray pair distribution function analysis reveals that this structural distortion is relieved when the electronic configuration of the dopant element cannot produce lone pair electrons. Furthermore, a decrease in the Grüneisen parameter with doping is experimentally confirmed, establishing a relationship between the stereochemical activity of lone pair electrons and the lattice anharmonicity. The observed “harmonic” behavior with doping suggests that lone pair electrons must be preserved to effectively suppress phonon transport in these systems.

Podocyte degenerative changes are common in various kidney diseases, and their accurate identification is crucial for pathologists to diagnose and treat such conditions. However, this can be a difficult task, and previous attempts to automate the identification of podocytes have not been entirely successful. To address this issue, this study proposes a novel approach that combines pathologists’ expertise with an automated classifier to enhance the identification of podocytopathies. The study involved building a new dataset of renal glomeruli images, some with and others without podocyte degenerative changes, and developing a convolutional neural network (CNN) based classifier. The results showed that our automated classifier achieved an impressive 90.9% f-score. When the pathologists used as an auxiliary tool to classify a second set of images, the medical group’s average performance increased significantly, from $91.4\pm 12.5$ % to $96.1\pm 2.9$ % of f-score. Fleiss’ kappa agreement among the pathologists also increased from 0.59 to 0.83. Conclusion: These findings suggest that automating this task can bring benefits for pathologists to correctly identify images of glomeruli with podocyte degeneration, leading to improved individual accuracy while raising agreement in diagnosing podocytopathies. This approach could have significant implications for the diagnosis and treatment of kidney diseases. Clinical impact: The approach presented in this study has the potential to enhance the accuracy of medical diagnoses for detecting podocyte abnormalities in glomeruli, which serve as biomarkers for various glomerular diseases.

In the original publication [...]

Introduction: Antiretroviral (ARV) drugs have improved prognoses for people living with HIV. However, HIV-associated neurocognitive disorders (HAND) persist despite undetectable viral loads. Some ARVs have been linked to neuropsychiatric effects that may contribute to HAND. Synapse loss correlates with cognitive decline in HAND and synaptic deficits may contribute to the neuropsychiatric effects of ARV drugs.Methods: Using an automated high content assay, rat hippocampal neurons in culture expressing PSD95-eGFP to label glutamatergic synapses and mCherry to fill neuronal structures were imaged before and after treatment with 25 clinically used ARVs.Results and Discussion: At a concentration of 10 μM the protease inhibitors nelfinavir and saquinavir, the non-nucleoside reverse transcriptase inhibitors etravirine and the 8-OH metabolite of efavirenz, the integrase inhibitor bictegravir, and the capsid inhibitor lenacapavir produced synaptic toxicity. Only lenacapavir produced synapse loss at the nanomolar concentrations estimated free in the plasma, although all 4 ARV drugs induced synapse loss at Cmax. Evaluation of combination therapies did not reveal synergistic synaptic toxicity. Synapse loss developed fully by 24 h and persisted for at least 3 days. Bictegravir-induced synapse loss required activation of voltage-gated Ca2+ channels and bictegravir, etravirine, and lenacapavir produced synapse loss by an excitotoxic mechanism. These results indicate that select ARV drugs might contribute to neuropsychiatric effects in combination with drugs that bind serum proteins or in disease states in which synaptic function is altered. The high content imaging assay used here provides an efficient means to evaluate new drugs and drug combinations for potential CNS toxicity.

In recent decades, extensive deforestation in tropical regions has dynamically reshaped forests and land cover. Driven by demands for intensified agriculture, rural settlement expansion, and urban growth, this transformation underscores the need for vigilant monitoring of vegetation and forest cover to comprehend global and local environmental shifts. This study focuses on the intricate interplay between deforestation and its impact on land surface temperature (LST) within Sabah's Kundasang highland. Analyzing years 1990, 2009, and 2021, the study employs Landsat 5 and Landsat 8 satellite data spanning three decades to decipher forest cover dynamics. Utilizing remote sensing techniques, it unveils the evolving relationship between deforestation, forest cover, and LST fluctuations, validated using Moderate Resolution Imaging Spectroradiometer (MODIS) insights from 1990 to 2021. Motivated by the scarcity of research on tropical deforestation's LST impact, the study's core aim is to establish a robust link between forest loss extent and ensuing thermal changes. The findings highlight a tangible influence of reduced vegetation on rising surface temperatures, necessitating a precise understanding of deforested areas and their thermal responses. Revealing a striking scenario, around 76% of Kundasang highland's forest cover transformed into agriculture and urban zones over 27 years. The study further uncovers a clear inverse relationship between LST and forest area in square kilometers, as well as the Normalized Difference Vegetation Index (NDVI). These findings provide valuable guidance for forest management, identifying vulnerable areas, while also empowering local governance to shape sustainable land management strategies.

The ~30 Ma to Recent Wrangell Arc (WA), Alaska is an ideal location to study subduction and slab-edge magmatism. However, the WA covers a huge area (~15,000 km2) and ~29% of the WA is covered by glaciers with rugged topography, making bedrock sampling challenging. We addressed these barriers with geochemical and geochronologic analyses on igneous cobbles collected from rivers encircling the WA. Results show that magmatism migrated southward and then northwestward, mirroring bedrock studies. Cobble geochemistry overlaps bedrock results, where calc-alkaline and adakitic cobbles are spatially and temporally ubiquitous in the WA, indicating that subduction and slab melting have been dominant processes. Intra-arc extension-related transitional-tholeiitic cobbles are not found in southwestern WA rivers and are limited in both bedrock and cobble data. The novel tandem cobble method closely matches the bedrock record in geochemical, temporal, and spatial contexts and can be used when bedrock access concerns and/or for characterizing watersheds.

Abstract Objective To determine prevalence and factors associated with flares post Coronavirus disease 2019 (COVID-19) mRNA vaccination in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and spondyloarthritis (SpA). Methods A retrospective multi-centre study was conducted (January 2021 to February 2022). Data were collected during index visit, defined as first post-vaccine visit in which the patient had a physician-defined flare, or if at least 3 months had elapsed since first vaccine dose, whichever came first. Factors associated with flares were identified using mixed effects Cox regression and expressed as hazard ratio (HR) and 95% confidence interval (CI). Results Total of 2377 patients were included (1563 RA, 415 PsA and 399 SpA). Among patients with RA, PsA and SpA, 21.3%, 24.1% and 21.8% experienced a flare respectively. Of those who experienced a flare, only 10.2%, 11.0% and 14.9% were severe in patients with RA, PsA and SpA respectively. Patients with low or moderate/high disease were more likely to flare compared to those in remission in patients with RA only (HR: 1.68, 95% CI 1.22–2.31; HR: 2.28, 95% CI 1.50–3.48, respectively). Receiving the Moderna vaccine was associated with a higher HR of flare compared to the Pfizer vaccine in patients with PsA only (HR: 2.21, 95% CI 1.20–4.08). Patients who had two vaccine doses were found to be less likely to flare (HR: 0.08, 95% CI 0.06–0.10). HRs of flares were not significantly different among RA, PsA and SpA. Conclusion About one-fifth of patients experienced a disease flare post COVID-19 mRNA vaccination, but most flares were non-severe. Patients with active disease prior to vaccination should be monitored closely for disease flares, especially in patients with RA.

Objective:Mammographic screening and management of breast cancer (BC) in elderly women are controversial and continue to be an important health problem. To investigate, through members of the Senologic International Society (SIS), the current global practices in BC in elderly women, highlighting topics of debate and suggesting perspectives.Materials and Methods:The questionnaire was sent to the SIS network and included 55 questions on definitions of an elderly woman, BC epidemiology, screening, clinical and pathological characteristics, therapeutic management in elderly women, onco-geriatric assessment and perspectives.Results:Twenty-eight respondents from 21 countries and six continents, representing a population of 2.86 billion, completed and submitted the survey. Most respondents considered women 70 years and older to be elderly. In most countries, BC was often diagnosed at an advanced stage compared to younger women, and age-related mortality was high. For this reason, participants recommended that personalized screening be continued in elderly women with a long life expectancy.In addition, this survey highlighted that geriatric frailty assessment tools and comprehensive geriatric evaluations needed to be used more and should be developed to avoid undertreatment. Similarly, multidisciplinary meetings dedicated to elderly women with BC should be encouraged to avoid under- and over-treatment and to increase their participation in clinical trials.Conclusion:Due to increased life expectancy, BC in elderly women will become a more important field in public health. Therefore, screening, personalized treatment, and comprehensive geriatric assessment should be the cornerstones of future practice to avoid the current excess of age-related mortality. This survey described, through members of the SIS, a global picture of current international practices in BC in elderly women.

In this study, the focus was to produce xanthan gum from pineapple waste using Xanthomonas campestris. Six machine learning models were employed to optimize fermentation time and key metabolic stimulants (KH2PO4 and NH4NO3). The production of xanthan gum was optimized using two evolutionary optimization algorithms, particle swarm optimization, and genetic algorithm while the importance of input features was ranked using global sensitivity analysis. KH2PO4 was the most important input and was found to be beneficial for xanthan gum production, while a limited amount of nitrogen was needed. The extreme learning machine model was the most adequate for modeling xanthan gum production, predicting a maximum xanthan yield of 10.34 g/l (an 11.9 % increase over the control) at a fermentation time of 3 days, KH2PO4 of 15 g/l, and NH4NO3 of 2 g/l. This study has provided important insights into the intelligent modeling of a biostimulated process for valorizing pineapple waste.

Unmanned aerial vehicles (UAVs), or drones, are transforming social science research by introducing innovative methodologies for data collection and analysis. This study systematically reviews the last two decades of literature to evaluate the role of UAVs across various social science disciplines, including archaeology, geography, public health, and disaster management. The analysis reveals that UAVs significantly enhance research capabilities by improving data accuracy, resolution, and accessibility, particularly in remote or challenging environments. Despite these advancements, challenges such as privacy concerns, ethical considerations, and technical limitations persist. The study underscores the need for interdisciplinary collaboration and the development of ethical frameworks to guide UAV integration in social sciences. The findings advocate for the continued exploration of UAV technology to address existing challenges and expand its applications, paving the way for future research that can further enhance the impact of UAVs on social science methodologies.

This study presents a deterministic mathematical model of monkeypox disease transmission dynamics with an age-structured human population divided into two subgroups of children (Group 1) and adults (Group 2). Two equilibrium points, monkeypox-free, E0, and a unique monkeypox-endemic equilibrium point, E1, are established. The age-structured monkeypox basic reproduction number, ℝ0, is computed using the next-generation matrix approach and established to be ℝ0=1.2448. The Lyapunov functions are constructed; together with LaSalle’s invariance principle, the monkeypox-free equilibrium point, E0, is established to be globally asymptotically stable whenever ℝ0≤1, as confirmed by the Lyapunov stability method, and the monkeypox-endemic equilibrium point, E1, is globally asymptotically stable whenever ℝ0>1. Sensitivity analysis of the threshold quantity ℝ0 is performed using the Latin hypercube sampling method and Pearson’s partial rank correlation coefficient, and the results showed that the parameters β11,β22,μ,ν1,Λ1,ν2 were the most sensitive to the spread of monkeypox infection in an age-structured population. It is, therefore, suggested that the rate of monkeypox infection can be reduced by ensuring that the rate of interaction between susceptible children and infected children and between susceptible adults and infected adults is minimized. Moreover, the spread of monkeypox infection can be curbed by emphasizing controls such as early diagnosis and treatment and hospitalization of critically ill infectives.

Abstract Patients living with advanced dementia (PLADs) face several challenges to attain the goal of avoiding prolonged dying with severe suffering. One is how to determine when PLADs’ current suffering becomes severe enough to cease all life‐sustaining treatments, including withdrawing assistance with oral feeding and hydrating, a controversial order. This article broadens the concept of suffering by including suffering that cannot be observed contemporaneously and the suffering of loved ones. Four paradigm shifts operationalize these concepts. During advance care planning, patients can judge which future clinical conditions would cause severe suffering. To decide when to allow patients to die, treating physicians/providers only need to assess if patients have reached patients' previously judged, qualifying conditions. Questions: Will this protocol prevent PLADs’ prolonged dying with suffering? Deter early‐stage dementia patients from committing preemptive suicide? Sway decision‐making surrogates from withholding life‐sustaining treatments from patients with middle‐stage dementia? Provoke providers’ resistance to relinquish their traditional, unilateral authority to determine patients’ suffering?

Abstract Many people dread prolonged dying with suffering in the terminal illness, advanced dementia. To successfully facilitate a timely dying, advance directives must be effective and acceptable. This article considers whether authorities, including treating physicians, can accept as moral, the effective intervention that ceases caregivers’ assistance with oral feeding and hydrating. The article presents eight criticisms and “alternate views” regarding ceasing assisted feeding/hydrating. It draws on perspectives from clinical medicine, law, ethics, and religion. The conflict is between (A) people's core beliefs that reflect cultural norms and religious teachings regarding what is moral versus (B) patients’ autonomous right of self‐determination and claim right to avoid suffering. The article presents each side as strongly as possible. Accepting the intervention as moral could allow patients a peaceful and timely dying from patients’ underlying disease. Confidence in future success can deter patients and their surrogates from considering a hastened dying in earlier stages of dementia.

Background This analysis aimed to evaluate the extent of treat-to-target (T2T) achievement after 1-year intensive treatment in patients enrolled to the APLAR SpA registry. Methods Patients who fulfilled the CASPAR2006 for psoriatic arthritis (PsA), and 2009ASAS criteria for axial spondylitis (AxSpA) were recruited. Current analysis included the first 143 patients reaching the 1-year timepoint across 7 Asia-Pacific regions (Hong Kong, Singapore, Korea, India, Pakistan, Qatar and Thailand). Results 79 patients with PsA(age: 52±13 years, 43(55%) male, disease duration: 8.0±8.3 years) and 64 patients with AxSpA (age:41±16 years, 48(75%) male, disease duration: 4.8±7.2 years) were included. There were significant improvement in Disease Activity in Psoriatic Arthritis (DAPSA) (22.1±14.4 at baseline vs 11.5±10.0 at 1-year, p

The preparation and processing of rodent brains for evaluation by immunohistochemistry is time-consuming. A large number of mouse brains are routinely used in experiments in neuroscience laboratories to evaluate several models of human diseases. Thus, methods are needed to reduce the time associated with processing brains for histology. A scalable method was developed to embed, section, and stain multiple mouse brains using supplies found in any common histology laboratory. Section collection schemes can be scaled to provide identical bregma locations between adjacent sections for immunohistochemistry, facilitating comprehensive, high-quality immunohistochemistry. As a result, sectioning and staining times are considerably reduced as sections from multiple blocks are stained simultaneously. This method improves on previous procedures and allows multiple embedding and subsequent immunostaining of brains easily with a dramatically reduced time requirement. Furthermore, we expand this method for use in numerous mouse tissues, rat brain tissue, and post-mortem human brain and arterial tissues. In summary, this procedure allows the processing of many rodent or human tissues from perfusion through microscopy in 10 days or less.

Background: Despite the widespread advocacy of the treat-to-target(T2T) strategy for managing psoriatic arthritis (PsA), a significant number of patients fail to achieve minimal disease activity (MDA) even with advanced therapies. While a universal definition of difficult-to-treat(D2T) PsA is absent, investigating the heterogeneity of D2T PsA within a real-life T2T-cohort can offer valuable insights into comprehending this concept. Methods: This analysis included the first 111 PsA patients enrolled in the APLAR SpA registry who underwent 1-year T2T management. They were recruited from 6 Asia-Pacific regions. D2T was defined as the failure to achieve MDA despite receiving [Formula: see text]1 conventional synthetic disease-modifying anti-rheumatic drugs(csDMARDs) and [Formula: see text]1 biologic/targeted synthetic DMARDs(b/tsDMARDs) over 6-months. Results: A total of 111 patients (mean age: 48± 13 years, 59 [53%] male, mean disease duration: 5.3± 7.3 years) were included. At baseline, the patients exhibited moderate disease activity, with only 35% achieving MDA. After 1-year, a significant improvement in Disease Activity in Psoriatic Arthritis (DAPSA) was observed (16.3± 14.0 at baseline vs 10.1± 9.7 at 1-year, p

Abstract Background The terminal illness of late-stage (advanced) Alzheimer’s and related dementias is progressively cruel, burdensome, and can last years if caregivers assist oral feeding and hydrating. Options to avoid prolonged dying are limited since advanced dementia patients cannot qualify for Medical Aid in Dying. Physicians and judges can insist on clear and convincing evidence that the patient wants to die—which many advance directives cannot provide. Proxies/agents’ substituted judgment may not be concordant with patients’ requests. While advance directives can be patients’ last resort to attain a peaceful and timely dying consistent with their lifelong values, success depends on their being effective and acceptable. A single flaw can provide opponents justification to refuse the directive’s requests to cease assisted feeding. Aim This article considers 24 common advance directive flaws in four categories. Process flaws focus on how patients express their end-of-life wishes. Content flaws reflect drafters’ selection of conditions and interventions, and how they are described. Inherent flaws can make advance directives unacceptable to authorities concerned about premature dying. Strategies are needed to compel physicians to write needed orders and to prevent third parties from sabotaging these orders after they are implemented. The article includes excerpts from “dementia-specific” directives or supplements that exemplify each flaw—mostly from the US and Europe. No directive critiqued here included an effective strategy to resolve this long-debated bioethical conflict: the past directive requests “Cease assisted feeding” but the incapacitated patient apparently expresses the desire to “Continue assisted feeding.” Some opponents to the controversial request, cease assisted feeding, use this conflict as a conceptual wedge to practice hard paternalism. This article proposes a protocol to prevent this conflict from emerging. These strategies may prevent authorities from requiring patients to fulfill authorities’ additional clinical criteria as a prerequisite to honor the requests in patients directives. Conclusion This critique of flaws may serve as a guide to drafting and to selecting effective and acceptable advance directives for dementia. It also poses several bioethical and clinical questions to those in authority: Does your paternalistic refusal to honor patients’ wishes respect their self-determination? Protect vulnerable patients from harm? Force patients to endure prolonged suffering? Violate the principles of bioethics? Violate the very foundation of patient-centered care?

Racism is a critical social problem, and we present a framework to guide professionals in engaging in anti-racist practices. Professionals on the frontlines in psychology and related fields such as social work and public health have a responsibility to engage in anti-racist practices. Part of the professional role must be to advocate for justice through increased proximity to the issues and engagement in anti-oppressive practices. The current discourse introduces a framework through which people working in psychology and other related professions can promote anti-racism work, highlighting the legal system for illustrative purposes. While some professionals in psychology may not have direct experience with the legal system, many of the individuals served by psychologists do (e.g., clients/patients, students, community members). Our framework is represented by the acronym STYLE (Self-examination, Talk about racism, Yield time to anti-racism work, Learn about structural racism, Evaluate policies and practices). The goal of STYLE is to expand anti-racism science and practice within psychology and related fields. We describe new roles for professionals in dismantling health inequities and offer specific pathways to develop critical partnerships toward this aim. STYLE explicitly encourages active, intentional involvement of affected community members in the development and evaluation of approaches to health services. To achieve equity and to promote individual and organizational growth in anti-racism and ultimately anti-oppression work, professionals must focus on changing their STYLE.

We examine the dynamics and stability of circumbinary particles orbiting around the Earth–Moon binary system. The moon formed close to the Earth (semimajor axis a _EM ≈ 3 R _⊕ ) and expanded through tides to its current day semimajor axis ( a _EM = 60 R _⊕ ). Circumbinary orbits that are polar or highly inclined to the Earth–Moon orbit are subject to two competing effects: (i) nodal precession about the Earth–Moon eccentricity vector and (ii) Kozai–Lidov oscillations of eccentricity and inclination driven by the Sun. While we find that there are no stable polar orbits around the Earth–Moon orbit with the current day semimajor axis, polar orbits were stable immediately after the formation of the Moon, at the time when there was a lot of debris around the system, up to when the semimajor axis reached about a _EM ≈ 10 R _⊕ . We discuss implications of polar orbits on the evolution of the Earth–Moon system and the possibility of polar orbiting moons around exoplanet–moon binaries.

We recently reported that messenger ribonucleic acid (mRNA) coronavirus disease 2019 (COVID-19) vaccination was associated with flares in 9% of patients with systemic lupus erythematosus (SLE). Herein, we focused our analysis on patients from a multi-ethnic Southeast Asian lupus cohort with the intention of identifying distinct phenotypes associated with increased flares after mRNA COVID-19 vaccination. Methods: Six hundred and thirty-three SLE patients from eight public healthcare institutions were divided into test and validation cohorts based on healthcare clusters. Latent class analysis was performed based on age, ethnicity, gender, vaccine type, past COVID-19 infection, interruption of immunomodulatory/immunosuppressive treatment for vaccination, disease activity and background immunomodulatory/immunosuppressive treatment as input variables. Data from both cohorts were then combined for mixed effect Cox regression to determine which phenotypic cluster had a higher risk for time to first SLE flare, adjusted for the number of vaccine doses. Results: Two clusters were identified in the test (C1 vs. C2), validation (C1′ vs. C2′) and combined (C1″ vs. C2″) cohorts, with corresponding clusters sharing similar characteristics. Of 633 SLE patients, 88.6% were female and there was multi-ethnic representation with 74.9% Chinese, 14.2% Malay and 4.6% Indian. The second cluster (C2, C2′ and C2″) was smaller compared to the first. SLE patients in the second cluster (C2 and C2′) were more likely to be male, non-Chinese and younger, with higher baseline disease activity. The second cluster (C2″) had more incident flares (hazard ratio = 1.4, 95% confidence interval 1.1–1.9, p = 0.014) after vaccination. A higher proportion of patients in C2″ had immunomodulatory/immunosuppressive treatment interruption for vaccination as compared to patients in C1″ (6.6% vs. 0.2%) (p < 0.001). Conclusion: We identified two distinct phenotypic clusters of SLE with different patterns of flares following mRNA COVID-19 vaccination. Caution has to be exercised in monitoring for post-vaccination flares in patients with risk factors for flares such as non-Chinese ethnicity, young age, male gender and suboptimal disease control at the time of vaccination.

Background: Studies have reported that female patients with spondyloarthritis have different disease courses and treatment responses compared to male patients. Whether patients’ sex is associated with a different outcome after receiving one-year of tight control, treat-to-target (T2T) strategy remains uncertain. Thus, this study aimed to evaluate the differences in the clinical response between male and female patients from the APLAR SpA Registry. Methods: Patients who fulfilled the CASPAR 2006 classification criteria for PsA and 2009 ASAS classification for axSpA were recruited. They received 1 year of protocolized treatment aiming at 1) MDA or DAPSA-LDA for PsA patients, and 2) ASDAS-LDA for axSpA patients. Patients were assessed every 3-monthly and treatment was escalated if target was not reached. Results: Ninety-one male (age: 45.6±16.1, 43 PsA, 48 axSpA) and 52 female (age: 49.2±13.4, 36 PsA, 16 axSpA) patients were included. There was no significant difference between the 2 sexes at baseline, except a higher ESR and more severe enthesitis in female patients. During the study period, the use of csDMARDs and NSAIDs decreased slightly, whilst the use of bDMARDs significantly increased across both sexes (Fig. 1a). Considering the whole cohort, there were significant improvement in disease activity in PsA after 1-year and disease activity in axSpA remained low. Despite similar bDMARDs use at 1-year, female PsA patients had a lower MDA achievement rate (36% in female vs 51% in male). Female patients also remained to have a higher physician global assessment score (2.61±1.76 in female vs 1.98±1.57 in male, p=0.03), greater functional impairment (HAQ: 0.54±0.57 in female vs 0.32±0.46 in male, p=0.01) and more severe enthesitis (SPARCC: 0.83±1.67 in female vs 0.16±1.09 in male, p=0.005) at 1-year. There was also a trend of higher perceived disease burden and peripheral involvement in female (Fig. 1b). Conclusion: There may be differential treat-to-target responses between male and female SpA patients. The causes of such differential characteristics should be further explored to potentially implement a sex-specific treat-to-target strategy for spondyloarthritis.

Objective:Therapeutic management of ductal carcinoma in situ (DCIS) is heterogeneous among countries worldwide, and some treatment indications are still controversial. To investigate DCIS management in different countries; identify both consensual practices and controversial topics; and survey opinions about the future management of DCIS.Materials and Methods:The Senologic International Society network members participated to an online survey using a questionnaire, between November 2021 and February 2022.Results:Twenty-two responses from 20 different countries showed that organized breast cancer screening programs were present for 87% participants, and DCIS cases represented 13.7% of all breast cancers. Most participants used the grade classification (100%), the morphological classification (78%) and performed immunohistochemistry assays (73%). In case of conservative treatment, the mean re-excision rate was 10.3% and clear margins of mean 2.5 mm were considered healthy. Radical mastectomy rate was 35.5% with a breast reconstruction rate of 53%. Tumor bed boost indications were heterogeneous, and 73% of participants indicated hormone therapy for hormone-positive DCIS. Surgery and radiotherapy omission for some low-risk DCIS were considered by 73% of participants. Multigene assays were used by 43% of participants. Concerning future changes in DCIS management, participants mostly answered surgical de-escalation (48%), radiotherapy de-escalation (35) and/or active surveillance for some cases (22%).Conclusion:This survey provided an overview of the current practices of DCIS management worldwide. It showed that some areas are rather consensual: incidence increases over time, treatment in young women, pathological classifications, definition of healthy margins, the skin-sparing mastectomy and immediate breast reconstruction. However, some topics are still debated and result in heterogeneous practices, such as evolution in the age of diagnosis, the benefit of de-escalation in low-risk DCIS among elderly women, indications for hormone therapy, radiotherapy omission, or multigene assays. Further evidence is needed to reach consensus on these points, and innovative approaches are still under evaluation in clinical trials. The International Senologic Society, by its members, encourages precision medicine and personalized treatments for DCIS, to avoid overtreatment and overdiagnosis, and provide better healthcare to women with DCIS.

Acute kidney injury (AKI) is a leading cause of morbidity in urinary tract infection (UTI). We aimed to identify simple biomarkers and bacterial virulence factors associated with AKI in a setting of upper UTI due to uropathogenic Escherichia coli (UPEC). We designed a cross-sectional study to analyse biomarkers of AKI in upper UTI patients. A total of 2758 patients presenting to a tertiary care center with symptoms of upper UTI were assessed for the presence of diabetes mellitus, AKI, blood group non-secretors, urine microscopy and hemogram. 300 patients with UPEC in bacterial culture were studied for bacterial virulence factors by phenotypic and genotypic methods and the patients were followed up for a minimum period of two weeks. Patients with diabetes mellitus, non-secretors, Urine microscopy (UM) score > 2 and higher (> 3.9) neutrophil-lymphocyte ratio (NLR) at initial presentation, were found to be significantly associated with AKI at presentation and predicted AKI at 7th and 14th day follow up. They were also significantly associated with need and increased duration of hospitalization. There was no association of virulence factors of UPEC with diabetes mellitus, AKI or need for hospitalization. However, virulence factors had a significant association (p

HIV-associated lipodystrophy (HIVLD) is a metabolic condition with an irregularity in the production of lipoprotein particles, and its occurrence varies among HIV-infected patients. MTP and ABCG2 genes have a role in the transport of lipoproteins. The polymorphisms of MTP -493G/T and ABCG2 34G/A affect its expression and influence the secretion and transportation of lipoproteins. Hence, we investigated the MTP -493G/T and ABCG2 34G/A polymorphisms in 187 HIV-infected patients (64 with HIVLD and 123 without HIVLD) along with 139 healthy controls using polymerase chain reaction (PCR)-restriction fragment length polymorphism and expression analysis using real-time PCR. ABCG2 34A allele showed an insignificantly reduced risk of LDHIV severity [P = 0.07, odds ratio (OR) = 0.55]. MTP -493T allele exhibited a non-significantly reduced risk for the development of dyslipidemia (P = 0.08, OR = 0.71). In patients with HIVLD, the ABCG2 34GA genotype was linked with impaired low-density lipoprotein levels and showed a reduced risk for LDHIV severity (P = 0.04, OR = 0.17). In patients without HIVLD, the ABCG2 34GA genotype was associated with impaired triglyceride levels with marginal significance and showed an increased risk for the development of dyslipidemia (P = 0.07, OR = 2.76). The expression level of MTP gene was 1.22-fold decreased in patients without HIVLD compared with that in patients with HIVLD. ABCG2 gene was upregulated 2.16-fold in patients with HIVLD than in patients without HIVLD. In conclusion, MTP -493C/T polymorphism influences the expression level of MTP in patients without HIVLD. Individuals without HIVLD having ABCG2 34GA genotype with impaired triglyceride levels may facilitate dyslipidemia risk.

Objectives To evaluate the association between anxiety, depression and resilience with overall health and functioning in axial spondyloarthritis (axSpA).Design Cross-sectional evaluation of baseline data from a prospective cohort study, with recruitment from January 2018 to March 2021.Setting Outpatient clinic in a tertiary hospital in Singapore.Participants Patients aged 21 years and above who were diagnosed with axSpA.Outcome measures The Hospital Anxiety and Depression Scale (HADS) was used for assessing anxiety and depression, 10-item Connor Davidson Resilience Scale (CD-RISC-10) for resilience, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for disease activity, Bath Ankylosing Spondylitis Functional Index (BASFI) for functional limitation and Assessment of SpondyloArthritis International Society Health Index (ASAS HI) for overall health and functioning. Univariable and multivariable linear regression analyses were performed to assess the association between anxiety, depression and resilience with health and functioning.Results We included 296 patients in this study. The median (IQR) score for HADS-Anxiety was 5.0 (2.0–8.0), with 13.5% and 13.9% having borderline abnormal and abnormal anxiety, respectively. The median (IQR) score for HADS-Depression was 3.0 (1.0–7.0), with 12.8% and 8.4% having borderline abnormal and abnormal depression, respectively. The median (IQR) CD-RISC-10 score was 29.0 (23.0–32.0) while the median (IQR) ASAS HI score was 4.0 (2.0–7.0). Apart from BASDAI, BASFI and disease duration, anxiety and depression were associated with overall health and functioning (β: 0.12, 95% CI 0.03, 0.20; β: 0.20, 95% CI 0.09, 0.31) in the multivariable linear regression. Level of resilience was not associated with health and functioning.Conclusion Anxiety and depression, but not resilience, were associated with poorer health and functioning. Clinicians could consider routinely screening for anxiety and depression in their patients, especially in patients with more severe symptoms.

Starting around 2008, there was rapid expansion of oil and natural gas (ONG) production into more heavily populated areas within the Dallas-Fort Worth metroplex in the Barnett Shale region of Texas. This colocation raised concerns regarding the effect of ONG activities on chemical levels in the air. In the current study, we examined the potential impacts of ONG activity on the types and concentrations of chemicals in ambient air in the Barnett Shale. Volatile organic compound (VOC) concentrations from 6–12 years (2008–2019) of hourly ambient air monitoring data from 15 monitors (4 monitors had ≥ 10 years of data) were compared to several metrics of ONG activity (number of active wells, natural gas production, condensate production) within a 2-mile radius of each monitor. Monitoring sites were also classified into urban, suburban, and rural areas as a surrogate for nearby vehicular emission sources. Analyses of this huge dataset showed that both peak and mean chemical concentrations of lighter alkane hydrocarbons (e.g., ethane) were most impacted by the number of gas wells. Levels of heavier alkanes (e.g., pentane) were increased by condensate production and at monitors located in areas with greater urbanicity, and therefore higher vehicular emissions. The levels of unsaturated alkynes (e.g., ethylene) were entirely driven by urbanicity and were unaffected by nearby ONG activity. The same pattern was seen with the ratio of iso:n-pentane, which is contrary to the findings of others and suggests an area for future research. Aromatic hydrocarbons were impacted by multiple emissions sources and did not show the same patterns as non-aromatic VOCs. No VOC concentrations were at levels of concern for human health or odor based on comparison to Texas air monitoring comparison values. Overall, ONG activities impact air quality, but this must be evaluated in the context of other emission sources such as automobiles.

Root morphological traits (RMTs) profoundly influence plant growth, resilience to abiotic stresses, and yield in soybean (Glycine max). In a comprehensive study spanning two consecutive years (2021–2022), the RMTs were assessed in 216 soybean accessions from 34 diverse origins. The investigation involved randomized batches with plants cultivated in PVC pipes filled with horticultural soil and harvested at the V2 growth stage. All the germplasms exhibited significant differences (p < 0.001) in all measured traits, i.e., total root length (TRL), root volume (RV), average diameter (AD), number of tips (NT), number of forks (NF), and tertiary total length (TTL). Among the top 5% performers in TRL, which, interestingly, were exclusively of Korean origin, germplasm IT115491 displayed an impressive average TRL value of 1426.24 cm. Notably, germplasms from Serbia and Korea predominantly occupied the upper AD quantile, with IT156262 exhibiting the highest AD value of 0.57 mm. A correlation analysis showed strong positive associations of TRL with RV (r = 0.85), NT (r = 0.84), NF (r = 0.96), and TTL (r = 0.88), whereas it had a negative association with AD (r = −0.25). A principal component analysis (PCA) showed a cumulative 95% of the total variance in the data in the first three principal components (PCs). PC1 (eigenvalue = 4.64) accounted for a 77.00% variance, with TRL, RV, NF, NT, and TTL exhibiting the highest associated eigenvectors. K-means clustering was performed with three clusters. Cluster 2 contained accessions with higher AD values, whereas Cluster 3 comprised accessions with increased TRL, NT, NF, and TTL, which mostly originated from Korea. Our findings offer targeted insights for plant breeders to optimize specific root traits and enhance crop performance across diverse environmental conditions by strategically targeting these clusters. Additionally, the influence of cultivar origin on root traits warrants further investigation, with implications for future breeding programs.

Proteins, other metabolites and many valuable synthetic products contain amide bonds and there is a need for more sustainable amide synthesis routes. Here the authors show an integrated next generation multi-catalytic system, merging nitrile hydratase enzymes with a Cu-catalysed N-arylation reaction in a single reaction vessel, for the construction of ubiquitous amide bonds.

Correlates of protection are key for vaccine development against any pathogen. In this paper we summarize recent information about correlates for vaccines against dengue, Ebola, influenza, pneumococcal, respiratory syncytial virus, rotavirus, shigella, tuberculosis and Zika virus.

Urinary tract infection (UTI) causes significant renal damage and disease severity is compounded by antimicrobial resistance (AMR) and other comorbidities in the patient. Blood group antigens secreted in body fluids (secretor status) are known to play a role in bacterial adhesion and we studied its influence on AMR in UTI. A total of 2758 patients with UTI were studied with urine culture, qualitative and semiquantitative urine microscopy, serum creatinine and secretor status in saliva samples by adsorption-inhibition method. Of these, AMR from 300 patients with E. coli infection were assessed as per CLSI 2019 guidelines and extended-spectrum beta-lactamase (ESBL) genes (bla TEM, bla CTX-M, bla SHV) and NDM1 genes were studied using TaqMan probes in Real-time polymerase chain reaction. Patients with UTI were followed up for two weeks. Female patients had higher predilection (57%) for E. coli infection while patients with diabetes or non-secretors had none. In our study, ESBL producers were seen in 62% of the E. coli isolates and fosfomycin had 100% susceptibility. Non-secretors were significantly associated with acute kidney injury (AKI), AMR and ESBL genes. Multidrug-resistance (MDR) was noted in 127/160 (79.4%) ESBL and 17/18 (94%) NDM1 gene encoding strains. Quantitative urine microscopy scoring predicted AKI both at presentation and at end of follow up. ESBL producers were common in our study population and non-secretors had a significant association with AMR genes. Urine microscopy scoring system may be a useful tool to predict AKI in patients with UTI.

Patients infected by the SARS-CoV-2 virus are commonly diagnosed with threatening liver conditions associated with drug-induced therapies and systemic viral action. RNA-Seq data from cells in bronchoalveolar lavage fluid from COVID-19 patients have pointed out dysregulation of kallikrein-kinin and renin-angiotensin systems as a possible mechanism that triggers multi-organ damage away from the leading site of virus infection. Therefore, we measured the plasma concentration of biologically active peptides from the kallikrein-kinin system, bradykinin and des-Arg9-bradykinin, and liver expression of its proinflammatory axis, bradykinin 1 receptor (B1R). We measured the plasma concentration of bradykinin and des-Arg9-bradykinin of 20 virologically confirmed COVID-19 patients using a liquid chromatography-tandem mass spectrometry-based methodology. The expression of B1R was evaluated by immunohistochemistry from post-mortem liver specimens of 27 COVID-19 individuals. We found a significantly higher blood level of des-Arg9-bradykinin and a lower bradykinin concentration in patients with COVID-19 compared to a healthy, uninfected control group. We also observed increased B1R expression levels in hepatic tissues of patients with COVID-19 under all hepatic injuries analyzed (liver congestion, portal vein dilation, steatosis, and ischemic necrosis). Our data indicate that des-Arg9-bradykinin/B1R is associated with the acute hepatic dysfunction induced by the SARS-CoV-2 virus infection in the pathogenesis of COVID-19.

Abstract Colon medullary adenocarcinoma (MAC) is a rare histologic subtype. Clinical presentation and cancer outcomes of MAC, compared to colon adenocarcinoma (AC), remain incompletely described. Annual age-adjusted incidence rates were computed using Surveillance, Epidemiology, and End Results (2002–2017). A cohort analysis using the National Cancer Database (2010–2016) compared patient characteristics in an unmatched dataset and prognostic characteristics in a 1:1 matched subset. Reported annual age-adjusted incidence of MAC has significantly increased, with an average annual percent change (APC) increase of 23.8% (95% CI: 19.2–28.6); concurrent AC incidence declined (APC: − 2.8, 95% CI: − 3.1 to − 2.8). Analyses of 1018 MAC and 210,784 AC unmatched patients showed that MAC patients were more often older, female, and white, with higher disease stage, poorly-differentiated tumors, right-sided laterality, and lymphovascular invasion (all p